Spinal cord injury (SCI) is one of the most disabling health problems facing adults today. Profound loss of muscle mass and strength contribute to impaired locomotor function and the development of chronic disability after SCI. Rehabilitation strategies that utilize activity based therapies, such as body weight supported treadmill training, have yielded encouraging results. The overall goal of this project is to identify pharmacological strategies that can enhance the therapeutic effect of rehabilitation interventions after SCI. Specifically, this Project will focus on the muscle growth factors, insulin-like growth factor I (IGF-I) and myostatin, and intracellular protease inhibitors developed and tested in projects 1 and 2. The experiments in this project will be primarily performed in rats with a contusion SCI. In Aim 1, we will determine the ability of a rehabilitation regime involving daily sessions of locomotor treadmill training (2x20min) to improve muscle strength, muscle endurance and the recovery of locomotor function in unloaded contusion SCI rats (removable cast) as well as unrestricted (or freely loading) SCI rats. Subsequently, in Aims 2&3 we will investigate the effect of increasing insulin-like growth factor-l (IGF-I) and inhibiting the negative growth regulator myostatin on the therapeutic efficacy of treadmill locomotor training in unloaded contusion SCI rats. In addition, since the pathways appear to be distinct we will examine whether the effects of modulating both muscle growth pathways will be additive. Since protein degradation appears to be responsible for the bulk of muscle loss during disuse and following SCI, we will also determine whether inhibiting protein degradation via specific drugs will facilitate the implementation of rehabilitation interventions and in particulariy increase the effectiveness of treadmill locomotor training in promoting locomotor recovery Finally, we will observe the effect of the most optimal intervention (growth factors and/or protease inhibitors) in an SCI model in which there is minimal supraspinal communication (complete transection SCI). RELEVANCE (See instructions): The results from these experiments will provide important preclinical data on whether modulation of muscle growth pathways and protease inhibitors can be successfully used in combination with rehabilitation interventions to facilitate the recovery of ambulatory function following SCI. Establishing the effectiveness of complementary treatment interventions in an animal model is a critical step in the translation to human studies.